VEGFR3gene structure, regulatory region, and sequence polymorphisms

Abstract

Vascular endothelial growth factor receptor 3 (VEGFR‐3) is required for cardiovascular development during embryogenesis. In adults, this receptor is expressed in lymphatic endothelial cells, and mutant VEGFR3 alleles have been implicated in human hereditary lymphedema. To better understand the basis of its specific endothelial lineage‐restricted expression, we have characterized the VEGFR3 gene and its regulatory 5′ flanking region. The human gene contains 31 exons, of which exons 30a and 30b are alternatively spliced. The VEGFR3 proximal promoter is TATA‐less and contains stretches of sequences homologous with the mouse Vegfr3 promoter region. In transfection experiments of cultured cells, the Vegfr3 promoter was shown to control endothelial cell‐specific transcription of downstream reporter genes. This result was further confirmed in vivo; in a subset of transgenic mouse embryos, a 1.6 kb Vegfr3 promoter fragment directed weak lymphatic endothelial expression of the LacZ marker gene. This suggests that endothelial cell‐specific elements occur in the proximal promoter, although further enhancer elements are probably located elsewhere. The sequence, organization, and variation in the VEGFR3 gene and its regulatory region provide important tools for the molecular genetic analysis of the lymphatic system and its disorders.—Iljin, K., Karkkainen, M. J., Lawrence, E. C., Kimak, M. A., Uutela, M., Taipale, J., Pajusola, K., Alhonen, L., Halmekyto, M., Finegold, D. N., Ferrell, R. E., Alitalo, K. VEGFR3 gene structure, regulatory region, and sequence polymorphisms. FASEB J. 15, 1028–1036 (2001)

A novel VEGFR3 mutation causes Milroy disease

“…Without functional data, the possibility remains that the identified change encodes a coding polymorphism. However, previous inquires by Iljin et al [2001] and Evans et al [2003] identified six and four polymorphisms, respectively, in the VEGFR3 coding region, none of which encoded the Q1020L missense mutation. Additionally, twelve other coding SNPs in the VEGFR3 gene (rs307821, rs307826, rs448012, rs744282, rs1049076, rs1049077, rs1049080, rs1130378, rs1130379, rs2270519, rs3736061, and rs3736062) are reported in the SNP database (NCBI) which also do not encode the Q1020L mutation.…”

“…VEGFR3 encodes a receptor tyrosine kinase that is expressed by lymphatic endothelial cells (LECs) [Kaipainen et al, 1995; Partanen et al, 2000] and is activated by the vascular endothelial growth factors VEGF‐C and VEGF‐D to mediate lymphangiogenesis [Veikkola et al, 2001]. The VEGFR3 gene is composed of 31 exons transcribed as two alternatively spliced transcripts encoding a protein with 7 immunoglobulin‐like repeat domains and 2 tyrosine kinase domains [Iljin et al, 2001]. Only 17 VEGFR3 mutations have been identified, and all mutations described localize to one of the two tyrosine kinase domains, illustrating the necessity of these domains in the signal transduction function of VEGFR3 [Ferrell et al, 1998; Irrthum et al, 2000; Karkkainen et al, 2000; Evans et al, 2003; Daniel‐Spiegel et al, 2005; Mizuno et al, 2005; Ghalamkarpour et al, 2006; Spiegel et al, 2006].…”

Physiological roles of the angiogenic factors during posthatching development period and adults in the quail lung

“…; Iljin et al . ). Although flt4 is thought to play a role in the maintenance of the lymphatic endothelium and/or in lymphangiogenesis in adults, several recent observations have suggested that flt4 may play a role in lung angiogenesis during embryonic development (Kaipainen et al .…”

Animal Models for the Molecular and Mechanistic Study of Lymphatic Biology and Disease

“…82,83,[86][87][88][89][90][91][92] The VEGFR-3 receptor, which is activated by VEGF-C and VEGF-D to mediate lymphangiogenesis, 93 is made up of an extracellular ligand-binding domain containing seven immunoglobulin homology regions, and two intracellular tyrosine kinase domains. 94 All VEGFR-3 mutations associated with Milroy's disease localize to one of these two tyrosine kinase domains, illustrating the necessity of these domains in the signal transduction function of VEGFR-3. 82 It is believed that the VEGFR-3 mutations in Milroy's disease result in defective VEGF-C and VEGF-D signaling due to dominant negative inhibition of VEGFR-3 autophosphorylation.…”